This invention relates to taxane derivatives. More particularly, this invention relates to derivatives of naturally occurring xylosyl substituted taxanes. These new compounds demonstrate surprising tubulin binding activity and cytotoxicity. "Although plant extracts have been used as anticancer agents for centuries, only a handful of plant-derived natural products have been found to show clinically useful activity, and taxol is clearly a member of this select group." (Kingston, "The Chemistry of Taxol, Pharmac. Ther., Vol. 52, pp. 1-34, 1 (1991); "Kingston"). Taxol, shown as composition 1 in FIG. 1, is a compound that occurs in the bark of the Pacific yew tree as well as other members of the taxus species. Taxol has been identified as having significant tubulin binding activity (Schiff, P. B. et al., "Promotion of Microtubule Assembly in vitro by Taxol," Nature, Vol. 277: 655-67 (February 1979)), and when delivered to the cell, it has significant cytotoxicity. Taxol was recently approved for the treatment of refractory ovarian cancer by the United States Food and Drug Administration.
Taxol is unusual among cytotoxic agents in that its method of action is through stabilization of polymerized tubulin, i e., "tubulin binding." Because this mechanism is different from conventional cytotoxic agents, it is a highly important addition to the arsenal of cancer therapy "weapons." Taxol is a complex molecule, and the specific attributes of its chemistry responsible for its tubulin binding activity have not been identified. Numerous taxol derivatives, having one or more substituted side groups, have been tested for tubulin binding activity with varying and unpredictable results. It is apparent from those tests that even minor changes in the taxol molecule may result in significantly different tubulin binding and cytotoxicity. Generally, the cytotoxic activity of most taxol analogs that have been studied parallel their tubulin-assembly activities. (Kingston, at 30.)
One of the few taxol related compounds that demonstrates enhanced tubulin binding is the compound known as "Taxotere," i.e. compound 2 shown in FIG. 1, which is a semisynthetic derivative of taxol with improved water solubility. "Taxotere" is a registered trademark of Rhone-Poulenc Rorer. Taxotere has been compared with taxol in phase I clinical trials. Although the structural differences between taxol 1 and Taxotere 2 are minor (see FIG. 1), enhanced in vitro tubulin binding activity is observed for Taxotere. Taxotere is slightly more active as a promoter of tubulin polymerization, 1.5 times more potent as an inhibitor of replication in mouse macrophage-like J774.2 cells and in P388 murine leukemia cells, and at least five-fold more potent in taxol-resistant tumor cells. (Pazdur, R. et al., "Phase I Trial of Taxotere: Five-Day Schedule", Journal of the National Cancer Institute, 1781, (1992)).
On the other hand, minor variations in the taxol molecule have frequently resulted in compounds that have significantly less tubulin binding activity and cytotoxicity. (For example, see compounds 10 through 15 in Table 2, p. 28 of Kingston). There are thousands of potential variations of the taxol molecule. "With few exceptions, changes in the taxane skeleton appear to reduce the activity of taxol." (Kingston, at 31.)
It is difficult to predict the relative potency of a taxol analog for microtubulin polymerization activity based on small changes in the overall structure. An examination of the Kingston review provides an overall view of the complexity of the structure-activity relationship of taxol analogs. It is clear that minor structural changes can cause major changes in tubulin binding activity and cytotoxicity. These changes can even completely eliminate any activity.
In addition, there are other factors, such as water solubility, toxicity, and pharmacokinetics which must be strongly considered when evaluating the efficacy of therapeutic agents for cancer treatment in general and the relative desirability of using particular agents in a given cancer treatment regimen. For example, certain recently reported negative side effects of Taxotere deserve further investigation. (Fumoleau, P. et al., "First Line Chemotherapy with Taxotere In Advanced Breast Cancer: A Phase II Study of the EORTC Clinical Screening Group," Proceedings of the American Society of Clinical Oncologists, Vol. 12, March 1993, p. 59 and Wanders, J. et al. "The EORTC ECTG Experience with Acute Hypersensitivity Reactions (HSR) in Taxotere Studies," Proceedings of the American Society of Clinical Oncologists, Vol. 12, March 1993, p. 73.) Taxol itself is difficult to deliver to the target site in vivo due to its poor solubility in water and the need to use delivery media which themselves have certain deficiencies.
The synthetic taxol derivatives described herein have not previously been described, and the literature does not suggest that they would exhibit cytotoxicity and enhanced tubulin assembly. Indeed, changes to taxol at the C-7 site including acylation, attachment of polar groups and epimerization reduce the activity of the molecule. Oxidation of taxol at the C-7 site also reduces activity significantly. (Kingston, at 30-31.)
The compounds of this invention have been tested for tubulin binding and cytotoxicity, using B-16 melanoma. In addition, the compounds have been screened by the National Cancer Institute using a number of cancer cell lines with surprisingly good results. The National Cancer Institute has selected these compounds for further testing as potential cancer-treating drugs.